The inflammatory response can resolve spontaneously or as a result of therapy (bronchodilator or anti-inflammatory drugs, such as corticosteroids). Low-grade inflammation may persist and result in a process called airway remodeling, manifested by permanent, irreversible structural changes such as submucosal fibrosis and airway smooth muscle hypertrophy. The mechanisms responsible for airway remodeling in allergic diseases are not clearly understood, but chemokines and cytokines such as TGF-β, a potent profibrotic cytokine, play important roles. Thus a very elegant, highly effective defensive system against infectious and parasitic organisms is “tricked” into responding to an innocuous substance, an allergen, as if it were harmful and initiates its defenses; the result is allergic airway disease.
Metabolic Functions of the Lung
The lungs are exposed to and metabolize a wide variety of xenobiotic substances. The endothelial cells within the lung capillary bed have a large surface area that receives very high blood flow, and lung endothelial cells have developed various mechanisms and cell surface receptors to metabolize xenobiotics. Most of the metabolic processing of inhaled or ingested xenobiotic compounds occurs enzymatically within the liver and intestinal tract with members of the cytochrome P-450 (CYP) enzyme families (e.g., CYP1, CYP2, CYP3). The lungs and other organs also selectively participate in the processing of xenobiotics and typically have lower levels of cytochrome P-450 enzymes. Prominent cytochrome P-450 enzymes in the lung include CYP1B1, CYP2B6, CYP2E1, CYP2J2, CYP3A5, and CYP1A1, the last of which is present in high levels in people who smoke cigarettes.
Drugs for the treatment of asthma and chronic obstructive pulmonary disease—such as corticosteroids, long-acting β2 receptor agonists, leukotriene receptor antagonists, and methylxanthines—are degraded enzymatically in the lungs. In addition, a wide array of endogenous substances are metabolized by endothelial cells within the pulmonary capillary bed, including vasoactive amines, cytokines, lipid mediators, and proteins.
Box 26.1 provides a list of compounds metabolized in the lung. Metabolism can occur • BOX 26.1 Compounds Metabolized in the Lungs (bronchoconstriction), eosinophil recruitment and activa-Vasoactiveaminestion (inflammation), and connective tissue remodeling. Cytokines
Symptoms of wheezing, coughing, and shortness of breath occur within minutes, followed by a late response of eosinophilia and airway inflammation.
through either intracellular or extracellular processing of endogenous substances that pass though the capillaries or by direct synthesis and secretion by endothelial cells. For example, angiotensin I is activated by angiotensinconverting enzyme, which is on the surface of endothelial cells. Serotonin, a vasoconstrictor, binds to a specific receptor on the surface of endothelial cells and is internalized and metabolized inside cells. Approximately 80% of the serotonin entering the lungs is metabolized in a single pass through the pulmonary capillary bed.